| Bioactivity |
PF-04447943 is a potent inhibitor of human recombinant PDE9A (IC50=12 nM) with >78-fold selectivity, respectively, over other PDE family members (IC50>1000 nM). |
| Target |
IC50: 12 nM (PDE9A) |
| Invitro |
Using recombinant human, rhesus, and rat PDE9A2 in a cell free assay PF-04447943 is shown to have a Ki of 2.8±0.26, 4.5±0.13, and 18.1±1.9 nM (n=4, 11 and 9 respectively). PF-04447943 is found to be highly selective over other PDE enzymes (PDE1, Ki=8600±2121 nM, n = 5; PDE2A3, Ki>99,000 nM; PDE3A, Ki>50,000 nM; PDE4A, Ki>29,000 nM; PDE5A, Ki=14,980±5025 nM, n=5; PDE6C, Ki=5324±2612 nM, n=4; PDE7A2, Ki>75,000 nM; PDE8A, Ki>50,000 nM; PDE10, Ki>51,250±20,056 nM, n=4; PDE11, Ki>80,000 nM) and no other significant activity at ~60 other receptors/enzymes. In HEK whole cells expressing rhesus PDE9A2, PF-04447943 inhibits ANP (0.3 μM) stimulated cGMP with an IC50 of 375±36.9 nM (n=16)[2]. |
| In Vivo |
Based on i.v. and p.o. dosing, pharmacokinetic studies with PF-04447943 in the rat indicates a Tmax of 0.3 h, T1/2 of 4.9 h, Cl of 21.7 mL/min/kg and an oral bioavailability of 47%. Thirty minutes following oral administration in rats (1-30 mg/kg), PF-04447943 concentrations dose-dependently increase in blood, brain and cerebrospinal fluid (CSF). The brain:plasma exposure ratios 30 min after dosing range from 0.13 at the 1 mg/kg dose to 0.33 at the 30 mg/kg dose. CSF levels are approximately 50% of brain levels. In mice, PF-04447943 (3, 10, 30 mg/kg p.o.) dose-dependently increases plasma and brain concentrations of PF-04447943 while the brain to plasma ratio ranged from 0.26 to 0.7 although this is not entirely dose dependent. CSF cGMP levels increase in a dose-dependent manner from a basal level of 3 pmol/mL to 13.3 pmol/mL (3.5-fold) at the 30 mg/kg dose. CSF cGMP levels also increase in a dose-dependent manner from a basal level of 3 pmol/mL in vehicle treated animals to 13.3 pmol/mL (3.5-fold) at the 30 mg/kg dose. CSF cGMP levels are elevated at all doses tested with a maximal effect of 3.5 fold increase above controls at 30 mg/kg[2]. |
| Name |
PF-04447943 |
| CAS |
1082744-20-4 |
| Formula |
C20H25N7O2 |
| Molar Mass |
395.46 |
| Appearance |
Solid |
| Transport |
Room temperature in continental US; may vary elsewhere. |
| Storage |
| Powder |
-20°C |
3 years |
|
4°C |
2 years |
| In solvent |
-80°C |
6 months |
|
-20°C |
1 month |
|
| Reference |
[1]. Kleiman RJ, et al. Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo. J Pharmacol Exp Ther. 2012 May;341(2):396-409. [2]. Hutson, P. H, et al. The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and |
